Lung cancer is caused by disordered growth of tracheal, bronchial and/or alveolar cells as a result of losing their normal functions. The number of people who die of lung cancer is the largest of the total of cancer deaths (17%), and worldwide about 1.3 million people die of lung cancer each year.
Treatment for lung cancer is divided into three major categories: surgical operation (surgical therapy), anticancer agent (chemotherapy) and radioactive irradiation (radiation therapy), but the effectiveness of treatment will vary depending on the tissue type of lung cancer. For example, although a definite diagnosis of lung cancer is made by a pathologist based on his cytohistopathological diagnosis on a microscope specimen, small cell lung cancer, which constitutes about 20% of lung cancer cases, has often reached an advanced stage at the time of discovery because it generally has a high grade of malignancy and will rapidly grow and spread and will often metastasize to other organs. For this reason, chemotherapy and/or radiation therapy is often used for treatment of this cancer, but the prognosis is poor because small cell lung cancer will often recur although it is relatively sensitive to these therapies. On the other hand, in the case of non-small cell lung cancer, which constitutes the remainder of about 80%, surgical therapy is considered for use until a certain stage, but there is little opportunity to use surgical operation in the subsequent stages where chemotherapy and/or radiation therapy is mainly used for treatment.
Thus, in either type of lung cancer, chemotherapy is an important option for treatment.
EGFR is a receptor tyrosine kinase and, when activated upon ligand binding, causes phosphorylation of tyrosine residues in the receptor's intracellular region and subsequently induces successive activation of cytoplasmic proteins, thereby facilitating cell differentiation and growth (Clinical Cancer Research, 12(18), 2006, p. 5268-5272). EGFR is found to be overexpressed in various malignant tumors (Journal of Cellular Physiology, 194(1), 2003, p. 13-19), and EGFR overexpression is shown to be a factor responsible for bad prognosis in cancer (Annals of Oncology, 15(1), 2004, p. 28-32, Journal of Clinical Oncology, 21(20), 2003, p. 3798-3807). In recent years, EGFR inhibitors have been observed to produce a high clinical effect on a limited population of non-small cell lung cancer patients, and it has been reported that active mutation of EGFR existed in such a patient segment (N. Engl. J. Med. 350, 2004, p. 2129-2139, Science 304, 2004, p. 1497-1500, Proc. Natl. Acad. Sci. 101, 2004, p. 13306-13311). As a result of a conformational change in the ATP-binding site of EGFR, this mutant EGFR is constitutively activated even in the absence of ligand stimulation, and thereby causes canceration of cells. In cancer cells having this mutant EGFR, it is known that they develop apoptosis by the action of gefitinib or erlotinib known as an EGFR inhibitor, resulting in a reduction of the tumor size (Nat. Rev. Cancer 7, 2007, p. 169-181).
ALK (Anaplastic Lymphoma Kinase) is a receptor tyrosine kinase and is a protein having a transmembrane region in the middle part, flanked by a tyrosine kinase region on the carboxyl-terminal side and an extracellular region on the amino-terminal side. It has previously been reported that full-length ALK is expressed in several types of cancer cells of ectodermal origin (e.g., neuroblastoma, glioblastoma, breast cancer, melanoma) (Non-patent Document 1). In some cases of human malignant lymphoma, it has also been reported that the ALK gene is fused with another gene (e.g., NPM gene, CLTCL gene, TFG gene) as a result of chromosomal translocation, and thereby produces an oncogenic fusion tyrosine kinase (Science, vol. 263, p. 1281, 1994; Blood, vol. 86, p. 1954, 1995; Blood, vol. 95, p. 3204, 2000; Blood, vol. 94, p. 3265, 1999). Also in the case of inflammatory myofibroblastic tumor, it is known that the ALK gene is fused with another gene (e.g., CARS gene, SEC31L1 gene) as a result of chromosomal translocation, and thereby produces a fusion tyrosine kinase (Laboratory Investigation, a journal of technical methods and pathology, vol. 83, p. 1255, 2003; International Journal of Cancer, vol. 118, p. 1181, 2006). Most of partner molecules (including EML4 (echinoderm microtubule associated protein like-4)) to be fused with ALK have a complex-forming domain, and the generated fusion products per se also appear to form complexes. This complex formation would induce uncontrol of ALK tyrosine kinase activity and abnormal activation of intracellular signals, thereby causing canceration (Cellular and Molecular Life Science, vol. 61, p. 2939, 2004; Nature Reviews Cancer, vol. 8, p. 11, 2008).
Moreover, recent reports have indicated the presence of a TPM4-ALK fusion protein in esophageal cancer by proteomics analysis procedures (World Journal of Gastroenterology, vol. 12, p. 7104, 2006; Journal Molecular Medicine, vol. 85, p. 863, 2007). Further, after the priority date of the present application, a fusion gene between EML4 and ALK was confirmed in specimens from lung cancer patients, and it was also reported that this EML4-ALK fusion gene has tumorgenicity and is a causal gene of cancer, and that inhibitors against its kinase activity suppress the growth of various cells where the EML4-ALK fusion protein is expressed (Patent Document 1 and Non-patent Document 2). These documents further show that inhibitors of the EML4-ALK fusion protein are useful as therapeutic agents for lung cancer in EML4-ALK polynucleotide-positive lung cancer patients.
Gefitinib and erlotinib mentioned above, which are EGFR inhibitors and are known as useful therapeutic agents for non-small cell lung cancer, have the following chemical structures.

Moreover, Patent Document 1 published after the priority date of the present application shows the following compounds (each being known as an ALK inhibitor) as examples of compounds having inhibitory activity against the EML4-ALK fusion protein, and it also discloses the actual values of their inhibitory activity against the EML4-ALK fusion protein (Patent Document 1). It should be noted that abbreviations for the following compounds are those used in Patent Document 1.

Their respective chemical names are: 4-[(3′-bromo-4′-hydroxyphenyl)amino]-6,7-dimethoxyquinazoline (also called WHI-P154) for compound A; N-[2-(3-chlorophenyl)ethyl]-2-[({[4-(trifluoromethoxy)phenoxy]acetyl}amino)methyl]-1,3-thiazole-4-carboxamide for compound B; 5-chloro-N4-[2-(isopropylsulfonyl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine for compound C; and 2-[(5-bromo-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)amino]-N-methylbenzenesulfonamide for compound D.
Moreover, in ALK fusion protein-expressing lymphoma cells, a compound having ALK inhibitory activity, WHI-P154, has been reported to inhibit cell growth and induce apoptosis (Non-patent Document 3). It should be noted that WHI-P154 is the same as compound A shown above.
Likewise, TAE684 represented by the following formula is known as an inhibitor of a fusion protein from a fusion gene between NPM gene and ALK gene. It should be noted that this compound is the same as compound C shown above.

TAE684 structurally differs from the compounds of the present invention in that the center ring sandwiched between two —NH groups is a chloro-substituted pyrimidine ring.
Moreover, TAE684 has been reported to inhibit the spread of anaplastic large cell lymphoma (ALCL) by its inhibitory activity against the NPM-ALK fusion protein (Non-patent Document 4). On the other hand, although it is described that compounds including TAE684 have inhibitory activity against focal adhesion kinase (FAK) and are thereby useful for preventing and/or treating non-small cell lung cancer and small cell lung cancer, there is no information about actual therapeutic effects on these lung cancers (Patent Document 2).
After the priority date of the present application, further reports were issued showing that EML4-ALK is expressed in non-small cell lung cancer cells (NCI-H2228), that TFG-ALK is expressed in non-small cell lung cancer patients, and that TAE684 inhibits the growth of non-small cell lung cancer cells (NCI-H2228) (Patent Document 1 and Non-patent Documents 5 and 6).
The supplemental data of Non-patent Document 6 shows that TAE684 has little growth inhibitory activity (inhibition rate: 7.5%) on HCC-827 cells (mutant EGFR protein-expressing cells) under the conditions shown in the document.
Further, after the priority date of the present application, a more recent report has indicated that TAE684 shows growth inhibitory activity on EGFR (L858R mutation)/BaF cells (Non-patent Document 7).
Patent Document 1: European Patent Publication No. EP 1914240
Patent Document 2: International Publication No. WO 2004/080980
Non-patent Document 1: International Journal of Cancer, vol. 100, p. 49, 2002
Non-patent Document 2: Nature, vol. 448, no. 2, p. 561, 2007
Non-patent Document 3: Laboratory Investigation, vol. 85, p. 1544, 2005
Non-patent Document 4: Proceedings of the National Academy of Science, vol. 104, no. 1, p. 270, 2007
Non-patent Document 5: Cell, vol. 131, p. 1190, 2007
Non-patent Document 6: Proceedings of the National Academy of Science, vol. 104, no. 50, p. 19936, 2007
Non-patent Document 7: American Association for Cancer Research Annual Meeting 2008 Proceedings, vol. 49, April 2008, p. 560, #2373